Distinct Actions of Insulin-Like Growth Factors (IGFs) on Placental Development and Fetal Growth: Lessons from Mice and Guinea Pigs
Introduction
Major complications of pregnancy occur in 19% of first pregnancies in Australia and other affluent nations [1]. They include pre-eclampsia (5–8%), pre-term birth (8%), and placental insufficiency with intrauterine growth restriction (IUGR, 6.4%). These complications are life-threatening to either the mother or her baby in more than 6% of pregnancies [1], [2].
The essential roles of the placenta in successful pregnancy place it as a major player in pregnancy complications. The human placenta has essentially two phases of development. The first is placental extravillous cytotrophoblast invasion of the decidua and its vasculature to sequester an adequate blood supply for placental and hence fetal growth. This occurs predominantly in the first half of gestation and permits sufficient blood flow into the placenta as well as its subsequent circumferential expansion. The second is terminal differentiation of villous trophoblast and the accompanying fetal placental vasculature to provide a maximal surface area for exchange between the maternal and fetal circulations [3].
Impaired trophoblast invasion has been implicated in several complications of pregnancy, such as unexplained miscarriage [4], pre-eclampsia and IUGR [5]. In pre-eclampsia and some miscarriages, for example, trophoblast invasion and colonisation of the spiral arterioles and the maternal decidual stroma is shallow, resulting in poor maternal blood flow to the placenta [4], [5]. In addition, impaired placental function is implicated in a significant proportion of IUGR cases [5], [6]. Furthermore, pregnancy complications, and IUGR in particular, have been associated with an increased risk for adult onset diseases including cardiovascular disease, hypertension and type 2 diabetes [7]. Therefore, determination of the molecular interactions regulating trophoblast invasion and placental function is essential to understanding the defects inherent in pregnancy complications and for the identification of potential targets for diagnostics and therapeutics.
Section snippets
Insulin-like growth factors and placental and fetal growth
Insulin-like growth factors (IGFs), both IGF-I and IGF-II, have been implicated in regulating fetal growth. Both in vivo and in vitro studies have revealed endocrine and autocrine/paracrine actions of IGFs in regulating placental function and fetal growth. Studies of mice carrying null mutations of the IGF-I or IGF-II genes have shown that expression of these growth factors is essential for normal fetal growth, since both IGF null mice are born at about 60% of the weight of wild type [8], [9].
IGF-II and trophoblast invasion
In women, evidence from in vitro studies and the localisation of IGF-II to extravillous cytotrophoblasts in tissue obtained in vivo [12], indicate that IGF-II induces invasion of the maternal decidua by these cells via a mechanism that is not well understood, but is thought to be independent of IGF1R [13]. The use of IGF-II analogues with specific receptor binding has shown that IGF-II-induced invasion by a trophoblast cell line is mediated through the IGF2R [14]. In mice, placentae from IGF-II
Endocrine actions of IGFS on the placenta
Currently it is suggested that IGF-II acts in an autocrine/paracrine fashion in the placenta. Although this is undoubtedly the case in both the fetus and placenta, it has become apparent that endocrine IGF-II in the mother can significantly impact the placenta. IGF-I expression in the placenta is absent or negligible, while IGF-II transcripts are abundant in most species examined, but particularly in those with an invasive placenta [11]. Therefore, IGF-I is likely to exert its effects in
Increasing IGF endocrine effects by IGF administration to the pregnant mother
We therefore proposed that increasing the abundance of IGFs in the pregnant guinea pig in early to mid gestation would promote fetal growth by specific actions in the placenta, since IGFs do not cross the placenta to the fetus. We selected guinea pigs for this investigation because their haemomonochorial placenta, although labyrinthine, is highly invasive and has similar growth dynamics to that of women [26], [27], [28]. In addition, guinea pigs deliver precocial neonates [26] and their IGF
The role of fetal IGFs
Within the fetus, IGF-I, modulated by its binding proteins, is thought to drive fetal growth. Thus cord blood IGF-I, but not IGF-II, concentration, particularly in association with IGFBP-1 and -2, is positively correlated with birth weight in human infants [37]. Cord blood soluble IGF2R concentration also increases as birth weight decreases in human infants. While the molar ratio of IGF-II to soluble IGF2R in cord blood is positively correlated with birth weight, IGF-II alone is not related to
Conclusion
The fact that IGFs are not known to cross the placenta indicates that positive effects of IGF administration to the pregnant mother on fetal growth are mediated by effects on both the placenta and mother. A summary of proposed actions for IGFs in mother, placenta and fetus is presented in Fig. 2.
IGF-II is an important regulator of growth and differentiation in many tissues throughout life and is expressed at high levels in the placenta. It has long been proposed that factors that promote
Conflict of interest
The authors do not have any potential or actual personal, political, or financial interest in the material, information, or techniques described in this paper.
Acknowledgements
We thank GroPep Pty Ltd for supply of recombinant IGFs. This work was supported by grants from Channel 7 Children's Research Foundation (J.A.O. and C.T.R.) and NHMRC (C.T.R.).
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